苦参 A，一种新型来源于苦参的槐定碱类生物碱，通过 ROS 介导的细胞焦亡和自噬具有治疗非小细胞肺癌的潜力。
Sophflarine A, a novel matrine-derived alkaloid from Sophora flavescens with therapeutic potential for non-small cell lung cancer through ROS-mediated pyroptosis and autophagy.
机构信息
Department of Anesthesiology, The First Affifiliated Hospital of Jinan University, Guangzhou 510000, PR China; Institute of Traditional Chinese Medicine & Natural Products, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, PR China; Guangdong Clinical Translational Center for Targeted Drug, Department of Pharmacology, School of Medicine, Jinan University, Guangzhou 510632, PR China.
Institute of Biopharmaceutical and Health Engineering, Shenzhen Key Laboratory of Gene and Antibody Therapy, State Key Laboratory of Chemical Oncogenomics, Shenzhen International Graduate School, Tsinghua University, Shenzhen, Guangdong 518055, PR China.
出版信息
Phytomedicine. 2023 Jul 25;116:154909. doi: 10.1016/j.phymed.2023.154909. Epub 2023 May 29.
BACKGROUND
Novel compounds and more efficient treatment options are urgently needed for the treatment of non-small cell lung cancer (NSCLC). The decoction of Sophora flavescens has been used to treat NSCLC in the clinic, and matrine-type alkaloids are generally considered to be the key pharmacodynamic material basis. But the previous study showed that common matrine-type alkaloids exhibit significant cytotoxicity only when at concentrations close to the millimolar (mM) level. The key antitumor alkaloids in S. flavescens seem to have not yet been revealed.
PURPOSE
The aim of this study was to screen water-soluble matrine alkaloid with novel skeleton and enhanced activity from S. flavescens, and to reveal the pharmacological mechanism of its therapeutic effect on NSCLC.
METHODS
Alkaloid was obtained from S. flavescens by chromatographic separation methods. The structure of alkaloid was determined by spectroscopic methods, and single-crystal X-ray diffraction. The mechanism of anti-NSCLC in vitro with cellular models was evaluated by MTT assay, western blotting, cell migration and invasion assay, plate colony-formation assay, tube formation assay, immunohistochemistry assay, hematoxylin and eosin staining. The antitumor efficacy in vivo was test in NSCLC xenograft models.
RESULTS
A novel water-soluble matrine-derived alkaloid incorporating 6/8/6/6 tetracyclic ring system, named sophflarine A (SFA), was isolated from the roots of S. flavescens. SFA had significantly enhanced cytotoxicity compared with the common matrine-type alkaloids, having an IC value of 11.3 μM in A549 and 11.5 μM in H820 cells at 48 h. Mechanistically, SFA promoted NSCLC cell death by inducing pyroptosis via activating the NLRP3/caspase-1/GSDMD signaling pathway, and inhibited cancer cell proliferation by increasing the ROS production to activate autophagy via blocking the PI3K/AKT/mTOR signaling pathway. Additionally, SFA also inhibited NSCLC cell migration and invasion by suppressing EMT pathway, and inhibited cancer cell colony formation and human umbilical vein endothelial cell angiogenesis. In concordance with the above results, SFA treatment blocked tumor growth in an A549 cell-bearing orthotopic mouse model.
CONCLUSION
This study revealed a potential therapeutic mechanism of a novel matrine-derived alkaloid, which not only described a rational explanation for the clinical utilization of S. flavescens, but also provided a potential candidate compound for NSCLC treatment.
背景
新型化合物和更有效的治疗方案迫切需要用于治疗非小细胞肺癌（NSCLC）。苦参的汤剂已在临床上用于治疗 NSCLC，而苦参型生物碱通常被认为是关键的药效物质基础。但之前的研究表明，常见的苦参型生物碱仅在接近毫摩尔（mM）水平的浓度时才表现出显著的细胞毒性。苦参中的关键抗肿瘤生物碱似乎尚未被揭示。
目的
本研究旨在从苦参中筛选具有新型骨架和增强活性的水溶性苦参碱，并揭示其治疗 NSCLC 的药理机制。
方法
通过色谱分离方法从苦参中获得生物碱。通过光谱方法和单晶 X 射线衍射确定生物碱的结构。通过 MTT 测定、western blot、细胞迁移和侵袭测定、平板集落形成测定、管形成测定、免疫组织化学测定、苏木精和伊红染色评估体外抗 NSCLC 的机制。在 NSCLC 异种移植模型中测试体内抗肿瘤功效。
结果
从苦参根部分离出一种新型的水溶性苦参衍生生物碱，命名为 sophflarine A（SFA），它含有 6/8/6/6 四环系统。与常见的苦参型生物碱相比，SFA 具有显著增强的细胞毒性，在 A549 和 H820 细胞中，48 小时的 IC 值分别为 11.3 μM 和 11.5 μM。在机制上，SFA 通过激活 NLRP3/caspase-1/GSDMD 信号通路诱导细胞焦亡，从而促进 NSCLC 细胞死亡，并通过阻断 PI3K/AKT/mTOR 信号通路增加 ROS 产生来抑制癌细胞增殖，从而激活自噬。此外，SFA 通过抑制 EMT 通路抑制 NSCLC 细胞迁移和侵袭，并抑制癌细胞集落形成和人脐静脉内皮细胞血管生成。与上述结果一致，SFA 治疗在 A549 细胞荷瘤原位小鼠模型中阻断了肿瘤生长。
结论
本研究揭示了一种新型苦参衍生生物碱的潜在治疗机制，不仅为苦参的临床应用提供了合理的解释，而且为 NSCLC 的治疗提供了一种潜在的候选化合物。
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